Project summary While exogenous DNA-mediated immune response contributes to host defense, excessive host cytoplasmic DNA can result in autoimmune diseases due to interferon overproduction. Taxilin alpha (TXLNA) has been implied in autoimmune disease caused by cytosolic DNA. However, the role of TXLNA in DNA-mediated innate immunity is unknown. Thus, it is pressing to elucidate the mechanisms of how TXLNA regulates DNA-induced innate immune signaling. This application proposes a hypothesis that TXLNA is a new signaling molecule in DNA-mediated, interferon-dependent innate immunity. Aim 1 will establish TXLNA as a TBK1 regulator in DNA-mediated innate immunity in vitro and in vivo. TXLNA deficiency will establish the requirement and specificity in TBK1-mediated interferon activation in response to DNA. Aim 2 will investigate the mechanisms by which TXLNA regulates TBK1 activity in DNA-mediated innate signaling pathway. We will examine several hypotheses of TXLNA-mediated TBK1 activation and recruitment to STING signalosome. The mechanistic concepts derived from this proposal will advance our current understanding of the regulatory mechanisms in DNA-mediated innate immunity. This project will also provide graduate and undergraduate students with opportunities for significant independent research in preparation for careers in biomedical science.